Huang Ming-Chyi, Schwandt Melanie L, Chester Julia A, Kirchhoff Aaron M, Kao Chung-Feng, Liang Tiebing, Tapocik Jenica D, Ramchandani Vijay A, George David T, Hodgkinson Colin A, Goldman David, Heilig Markus
1] Department of Psychiatry, Taipei City Psychiatric Center, Taipei City Hospital, Taipei, Taiwan [2] Department of Psychiatry, School of Medicine, Taipei Medical University, Taipei, Taiwan.
Laboratory of Clinical and Translational Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
Neuropsychopharmacology. 2014 Jul;39(8):2029-38. doi: 10.1038/npp.2014.55. Epub 2014 Mar 7.
Alcohol withdrawal is associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction. The FKBP5 gene codes for a co-chaperone, FK506-binding protein 5, that exerts negative feedback on HPA axis function. This study aimed to examine the effects of single-nucleotide polymorphisms (SNPs) of the FKBP5 gene in humans and the effect of Fkbp5 gene deletion in mice on alcohol withdrawal severity. We genotyped six FKBP5 SNPs (rs3800373, rs9296158, rs3777747, rs9380524, rs1360780, and rs9470080) in 399 alcohol-dependent inpatients with alcohol consumption 48 h before admission and recorded scores from the Clinical Institute Withdrawal Assessment-Alcohol revised (CIWA-Ar). Fkbp5 gene knockout (KO) and wild-type (WT) mice were assessed for alcohol withdrawal using handling-induced convulsions (HICs) following both acute and chronic alcohol exposure. We found the minor alleles of rs3800373 (G), rs9296158 (A), rs1360780 (T), and rs9470080 (T) were significantly associated with lower CIWA-Ar scores whereas the minor alleles of rs3777747 (G) and rs9380524 (A) were associated with higher scores. The haplotype-based analyses also showed an association with alcohol withdrawal severity. Fkbp5 KO mice showed significantly greater HICs during withdrawal from chronic alcohol exposure compared with WT controls. This study is the first to show a genetic effect of FKBP5 on the severity of alcohol withdrawal syndrome. In mice, the absence of the Fkbp5 gene enhances sensitivity to alcohol withdrawal. We suggest that FKBP5 variants may trigger different adaptive changes in HPA axis regulation during alcohol withdrawal with concomitant effects on withdrawal severity.
酒精戒断与下丘脑 - 垂体 - 肾上腺（HPA）轴功能障碍有关。FKBP5基因编码一种辅助伴侣蛋白，即FK506结合蛋白5，它对HPA轴功能发挥负反馈作用。本研究旨在探讨FKBP5基因单核苷酸多态性（SNP）在人类中的影响以及Fkbp5基因缺失对小鼠酒精戒断严重程度的影响。我们对399名酒精依赖住院患者进行了6个FKBP5 SNP（rs3800373、rs9296158、rs3777747、rs9380524、rs1360780和rs9470080）的基因分型，这些患者在入院前48小时有饮酒行为，并记录了修订版临床研究所酒精戒断评估（CIWA - Ar）的评分。对Fkbp5基因敲除（KO）小鼠和野生型（WT）小鼠在急性和慢性酒精暴露后，通过处理诱导惊厥（HIC）评估酒精戒断情况。我们发现rs3800373（G）× rs9296158（A）、rs1360780（T）和rs9470080（T）的次要等位基因与较低的CIWA - Ar评分显著相关，而rs3777747（G）和rs9380524（A）的次要等位基因与较高评分相关。基于单倍型的分析也显示与酒精戒断严重程度有关。与WT对照相比，Fkbp5 KO小鼠在慢性酒精暴露戒断期间表现出明显更多的HIC。本研究首次表明FKBP5对酒精戒断综合征严重程度有遗传影响。在小鼠中，Fkbp5基因缺失增强了对酒精戒断的敏感性。我们认为，FKBP5变体可能在酒精戒断期间触发HPA轴调节的不同适应性变化，同时对戒断严重程度产生影响。
